Roles of Bak and Sirt3 in Paraquat-Induced Cochlear Hair Cell Damage.
Roles of Bak and Sirt3 in Paraquat-Induced Cochlear Hair Cell Damage.
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DOI：
10.1007/s12640-021-00366-6
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发表时间：
2021-08
影响因子：
3.7
通讯作者：
Salvi R
中科院分区：
文献类型：
--
作者：
Ding D;Prolla T;Someya S;Manohar S;Salvi R
百草枯是一种超氧化物生成物，会损害耳蜗组织，导致耳毒性听力丧失。这项研究的目的是确定Bak基因的缺失是否会降低百草枯的耳毒性，或者SIRT3的缺失是否会增加百草枯的耳毒性。SIRT3可以延缓热量限制下的年龄相关性听力损失。我们用百草枯处理BAK+/−、BAK−/−、SIRT3+/−、SIRT3−/−和WT小鼠出生后第3天的耳蜗培养物来验证这两个假说，并将结果与标准的百草枯耳中毒模型进行比较。百草枯可损伤神经纤维，并呈剂量依赖性地破坏大鼠的外毛细胞和内毛细胞。当剂量为10μM时，大鼠耳蜗基底部毛细胞开始丢失，当剂量从50μM增加到500 M时，毛细胞丢失在耳蜗基底部附近增加，并向耳蜗尖扩散。大鼠OHC损失始终大于IHC损失。出乎意料的是，在所有类型的小鼠中，百草枯引起的毛细胞损伤在耳蜗尖附近最大，在底部附近最小。这种不同寻常的损害梯度与百草枯治疗的大鼠以及其他耳毒性药物治疗的小鼠和大鼠的情况相反。然而，在所有品系的小鼠中，百草枯引起的OHC损失总是大于IHC损失。与我们的假设相反，Bak缺陷小鼠比WT小鼠(Bak−/−>；Bak+/−>；WT)更容易受到百草枯耳毒性的影响，这表明Bak对毛细胞应激具有保护作用。此外，与预期相反，SIRT3缺陷小鼠与WT小鼠没有显著差异，可能是因为在百草枯治疗之前，SIRT3表达的小鼠没有在实验中上调SIRT3。我们的结果首次显示了小鼠耳毒性损伤的梯度，即耳蜗尖比耳蜗底更大。
Paraquat, a superoxide generator, can damage the cochlea causing an ototoxic hearing loss. The purpose of the study was to determine if deletion of Bak, a pro-apoptotic gene, would reduce paraquat ototoxicity or if deletion of Sirt3, which delays age-related hearing loss under caloric restriction, would increase paraquat ototoxicity. We tested these two hypotheses by treating postnatal day 3 cochlear cultures from Bak+/−, Bak−/−, Sirt3+/−, Sirt3−/− and WT mice with paraquat and compared the results to a standard rat model of paraquat ototoxicity. Paraquat damaged nerve fibers and dose-dependently destroyed rat outer hair cells (OHCs) and inner hair cells (IHCs). Rat hair cell loss began in the base of the cochlea with a 10 μM dose and as the dose increased from 50 to 500 μM, the hair cell loss increased near the base of the cochlea and spread towards the apex of the cochlea. Rat OHC losses were consistently greater than IHC losses. Unexpectedly, in all mouse genotypes, paraquat-induced hair cell lesions were maximal near the apex of the cochlea and minimal near the base. This unusual damage gradient is opposite to that seen in paraquat-treated rats and in mice and rats treated with other ototoxic drugs. However, paraquat always induced greater OHC loss than IHC loss in all mouse strains. Contrary to our hypothesis, Bak deficient mice were more vulnerable to paraquat ototoxicity than WT mice (Bak−/−>Bak+/−>WT), suggesting that Bak plays a protective role against hair cell stress. Also, contrary to expectation, Sirt3 deficient mice did not differ significantly from WT mice, possibly due to the fact that Sirt3 was not experimentally upregulated in Sirt3-expressing mice prior to paraquat treatment. Our results show for the first time a gradient of ototoxic damage in mice that is greater in the apex than the base of the cochlea.
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影响因子：
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